Minimum effective concentration of ropivacaine for ultrasound-guided transmuscular quadratus lumborum block in total hip arthroplasty: a randomized clinical trial.

OBJECTIVE: This trial aimed to identify the Minimum Effective Concentration (MEC90, defined as the concentration which can provide successful block in 90% of patients) of 30 mL ropivacaine for single-shot ultrasound-guided transmuscular Quadratus Lumborum Block (QLB) in patients undergoing Total Hip Arthroplasty (THA). METHODS: A double-blind, randomized dose-finding study using the biased coin design up-and-down sequential method, where the concentration of local anesthetic administered to each patient depended on the response from the previous one. Block success was defined as a Numeric Rating Scale (NRS) score during motion ≤ 3 at 6 hours after arrival in the ward. If the block was successful, the next subject received either a 0.025% smaller dose (probability of 0.11) or the same dose (probability of 0.89); otherwise, the next subject received a 0.025% higher ropivacaine concentration. MEC90, MEC95 and MEC99 were estimated by isotonic regression, and the corresponding 95% Confidence Intervals (95% CIs) were calculated by the bootstrapping method. RESULTS: Based on the analysis of 52 patients, MEC90, MEC95, and MEC99 of ropivacaine for QLB were estimated to be 0.352% (95% CI 0.334-0.372%), 0.363% (95% CI 0.351-0.383%), and 0.373% (95% CI 0.363-0.386%). The concentration of ropivacaine at 0.352% in a volume of 30 ml can provide a successful block in 90% of patients. CONCLUSIONS: For ultrasound-guided transmuscular QLB in patients undergoing THA, 0.352% ropivacaine in a volume of 30 ml can provide a successful block in 90% of patients. Further dose-finding studies and large sample size are required to verify the concentration.

Minimum effective concentration of ropivacaine for ultrasound-guided transmuscular quadratus lumborum block in total hip arthroplasty: a randomized clinical trial

Abstract Objective: This trial aimed to identify the Minimum Effective Concentration (MEC90, defined as the concentration which can provide successful block in 90% of patients) of 30 mL ropivacaine for single-shot ultrasound-guided transmuscular Quadratus Lumborum Block (QLB) in patients undergoing Total Hip Arthroplasty (THA). Methods: A double-blind, randomized dose-finding study using the biased coin design up-and-down sequential method, where the concentration of local anesthetic administered to each patient depended on the response from the previous one. Block success was defined as a Numeric Rating Scale (NRS) score during motion ≤ 3 at 6 hours after arrival in the ward. If the block was successful, the next subject received either a 0.025% smaller dose (probability of 0.11) or the same dose (probability of 0.89); otherwise, the next subject received a 0.025% higher ropivacaine concentration. MEC90, MEC95 and MEC99 were estimated by isotonic regression, and the corresponding 95% Confidence Intervals (95% CIs) were calculated by the bootstrapping method. Results: Based on the analysis of 52 patients, MEC90, MEC95, and MEC99 of ropivacaine for QLB were estimated to be 0.352% (95% CI 0.334-0.372%), 0.363% (95% CI 0.351-0.383%), and 0.373% (95% CI 0.363-0.386%). The concentration of ropivacaine at 0.352% in a volume of 30 ml can provide a successful block in 90% of patients. Conclusions: For ultrasound-guided transmuscular QLB in patients undergoing THA, 0.352% ropivacaine in a volume of 30 ml can provide a successful block in 90% of patients. Further dose-finding studies and large sample size are required to verify the concentration.

Relationship Between Daily Dose of Everolimus and Treatment Effect in Patients With Luminal HER2-negative Metastatic Breast Cancer.

BACKGROUND/AIM: Everolimus (EVE)-based treatment is an option for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), but a predictive marker has not yet been established. The recommended dose of EVE in combination with endocrine therapy is 10 mg/day, but due to adverse effects, patients are frequently forced to reduce the dose. However, the correct maintenance dose to achieve a therapeutic effect is still under debate. Employing real-world data, we examined clinicopathological factors to predict the efficacy of EVE-based treatment, particularly focusing on daily dose intensity (DDI). PATIENTS AND METHODS: Ninety-five patients with MBC who received EVE-based treatment in combination with exemestane during the period from 2014 to 2022 were retrospectively investigated. Doses of EVE were reduced as needed and DDI was calculated with total doses of EVE and the duration of the treatment. RESULTS: Mean time-to-treatment-termination (TTT) was 25.4 weeks. Patients with tumors with a high Ki67 labeling index, low absolute lymphocyte count, and small DDI of EVE had significantly shorter TTT (p=0.006, 0.043, and 0.030, respectively). When patients were categorized based on DDI of EVE, patients with DDI ≤5 mg/day had significantly shorter TTT (p=0.002). There were no correlations between RDI and factors such as age, body weight, and numbers of previous treatments for MBC. CONCLUSION: Maintaining a DDI of at least 5 mg/day seems crucial to achieving a therapeutic effect. Our data might be useful for determining the dosage of EVE in clinical practice.

Effective Dose Range of Intrathecal Isobaric Bupivacaine to Achieve T5-T10 Sensory Block Heights for Elderly and Overweight Patients: An Observational Study.

Background and Objectives: The dose selection for isobaric bupivacaine determines the success of spinal anesthesia (SA). A dose higher than the optimal dose causes high SA, whereas an underdose leads to inadequate spread of cephalad. As it involves anatomical and physiological alterations, the dosing should be reduced with advancing age and body mass index values. Therefore, this study aimed to demonstrate the association between the isobaric bupivacaine dose and block height, and to determine the dose intervals of bupivacaine to achieve the T5-T10 sensory block with a low probability of high SA in elderly and overweight patients. Material and Methods: This retrospective observational study recruited 1079 adult patients who underwent SA with 0.5% isobaric bupivacaine from 2018 to 2021. The patients were divided into four categories: category 1 (age < 60, BMI < 25), category 2 (age < 60, BMI ≥ 25), category 3 (age ≥ 60, BMI < 25), and category 4 (age ≥ 60, BMI ≥ 25). The bupivacaine dose and sensory block height (classified into three levels: high (T1-T4), favorable (T5-T10), and low (T11-L2)) were recorded. Results: The sensory block level increased significantly with increasing doses of bupivacaine for patients in categories 1 and 2. The suggested dose ranges for the favorable block heights were 15-17 and 10.5-16 mg in patient categories 1-2 and 3-4, respectively. In these dose ranges, the probability range of high SA was 10-15%. Conclusions: The sensory block height following SA was associated with the bupivacaine dose in patients aged <60 years. Regardless of the BMI, the suggested dose ranges of 0.5% isobaric bupivacaine are 15-17 mg (3.0-3.4 mL) and 10.5-16 mg (2.1-3.2 mL) for patients aged <60 and ≥60 years, respectively.

Amoxicillin/Metronidazole Dose Impact as an Adjunctive Therapy for Stage II - III Grade C Periodontitis (Aggressive Periodontitis) at 3- And 6-Month Follow-Ups: a Systematic Review and Meta-Analysis.

Objectives: This systematic review and meta-analysis study sought to review the efficacy of amoxicillin/metronidazole dose and duration time in the treatment of stage II - III grade C periodontitis (aggressive periodontitis) after current follow-up. Material and Methods: An electronic search of the literature was performed in three main databases for relevant articles published until 31th of December 2021. According to the PRISMA statement, the extracted data from selected articles were pooled. The weighted mean difference (MD) and 95% confidence interval (CI) of clinical attachment level (CAL) gain and probing depth (PD) reduction at 3 and 6 months of follow-up were calculated. The heterogeneity of the data was evaluated by the I2 test. Results: The results of six randomized clinical trials revealed significant improvement of clinical parameters in moderate and severe pockets. Prescription of 400 to 500 mg metronidazole caused significant CAL gain changes just in moderate pockets (MD = 1.82; 95% CI = 1.11 to 2.53; P < 0.05). Conclusions: Amoxicillin/metronidazole has positive short-term effects as an adjunct to scaling and root planning for treatment of stage II - III grade C periodontitis. Higher doses of metronidazole (400 to 500 mg) are required for optimal efficacy regarding clinical attachment level gain.

Determination of the minimum effective volume of bupivacaine for ultrasound-guided infraclavicular brachial plexus block: a prospective, observer-blind, controlled study.

BACKGROUND: We aimed to determine the minimum effective volume (MEV) of 0.5% bupivacaine for infraclavicular brachial plexus block. METHODS: We assigned patients to volume groups consisting of five consecutive patients. Local anesthetic was sequentially reduced from a starting dose of 30 mL by 2 mL to form the volume groups. Five patients were included in each volume group, and at least 3 of 5 injections had to be successful to consider the volume of the anesthetic as sufficient. The study ended when the anesthetic volume of a group was determined to be unsuccessful (two or fewer successful blocks). Block was successful if the patient reported a sensorial block score of 7 or more on an 8-point scale and sensorial and motor block's total score of 14 on a 16-point scale. RESULTS: The MEV of 0.5% bupivacaine for infraclavicular brachial plexus block was 14 mL. A successful block was achieved in all patients (n = 45) in 9 volume groups, which received 30 mL down to 14 mL. Three blocks were unsuccessful in the 12-mL group. Time to onset of block and time to first postoperative anesthetic administration was 15 (10-15) min and more than 24 h in the 30-mL bupivacaine group, but 40 (30-45) min and 14 (10-24) h were determined for the 14-mL group, respectively. CONCLUSIONS: The MEV of 0.5% bupivacaine for ultrasound-guided infraclavicular brachial plexus block was 14 mL. However, this low-dose block has a long onset time of 40 (30-45) min on average.

Population pharmacokinetic and exposure-response analysis of eptinezumab in the treatment of episodic and chronic migraine.

Eptinezumab is a humanized mAb that targets calcitonin gene-related peptide and is under regulatory review for the prevention of episodic and chronic migraine (EM, CM). It is important to determine whether exposures achieved with intravenous (IV) administration of eptinezumab achieve desired pharmacologic effects. Population pharmacokinetics, including dose- and exposure-response analyses, were performed using patient-level data from the eptinezumab clinical trial program with IV doses ranging from 10 to 1000 mg in pharmacokinetic analyses or 10 to 300 mg in phase 2/3 clinical studies in patients with EM or CM. Exposure-response analysis explored the relationship between eptinezumab exposure metrics and efficacy parameters including monthly migraine days. The pharmacokinetic profile of eptinezumab was characterized by rapid attainment of maximum plasma concentration (ie, end of IV administration) and a terminal half-life of 27 days. Covariate analysis found that patient characteristics had no clinically significant effects on pharmacokinetic parameters and were insufficient to influence dosing. Dose- and exposure-response analyses found exposure with single doses ≥100 mg was associated with greater efficacy compared with doses ≤30 mg and a plateau of effect between 100 and 300 mg. A saturable inhibitory Emax model found the exposure over 12 weeks produced by single-dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy (EC90 ). This pharmacokinetic analysis of eptinezumab supports dosing every 12 weeks with no adjustment for patient characteristics, including exposures associated with 100- or 300-mg doses producing optimal efficacy effects. The similar efficacy profiles support 100 mg as the lowest effective dose of eptinezumab.

A randomized, open labeled study comparing the serum levels of cobalamin after three doses of 500 mcg vs. a single dose methylcobalamin of 1500 mcg in patients with peripheral neuropathy.

BACKGROUND: Vitamin B12 deficiency has been associated with peripheral neuropathy, loss of sensation in the peripheral nerves, and weakness in the lower extremities. Methylcobalamin is the most effective analogue of vitamin B12 used to treat or prevent the complications associated with vitamin B12 deficiency. The current study aimed to compare the serum cobalamin levels after administration of two different regimes of methylcobalamin in peripheral neuropathy patients. METHODS: The present study was a prospective, randomized, comparative study. The study consisted of two parallel groups, group A (methylcobalamin 500 µg injection intramuscularly three times a week) and group B (methylcobalamin 1500 µg injection intramuscularly once a week). A control group of healthy volunteers was also included. RESULTS: A total of 24 patients (12 in each group) were included in the study. Five healthy volunteers were also included as a control in each group. At the end of treatment, serum cobalamin levels were significantly (P = 0.028) higher in group A (1892.08 ± 234.50) as compared with group B (1438.5 ± 460.32). The serum cobalamin levels in Group A healthy volunteers were also two times higher than that of group B (P = 0.056). Both the LANSS scale and DN4 questionnaire reported similar results at end of treatment. CONCLUSIONS: The 500 µg methylcobalamin thrice weekly regime is more effective in increasing the serum cobalamin levels as compared to the 1500 µg methylcobalamin once weekly regime.

Comparison of Two Different Volumes of Ropivacaine Used in Nerve Stimulator Guided Inter-scalene Block for Arthroscopic Shoulder Surgery - A Randomized Controlled Trial.

BACKGROUND: This study was conducted to compare the analgesic efficacy of 10 ml versus 20 mL of 0.5% ropivacaine in nerve stimulator guided interscalene brachial plexus block, in patients undergoing arthroscopic shoulder surgery. METHODS: A total of 70 American Society of Anesthesiologists physical status classes 1 and 2 patients, aged 18-65 years, undergoing unilateral arthroscopic shoulder surgery, were randomized into two groups. Group A received single shot inter-scalene block with 20 mL of 0.5% ropivacaine whereas Group B received the same with 10 mL. The primary outcome was difference in the total postoperative fentanyl consumption over 24 h. Secondary outcomes were difference in block onset, intra-operative hemodynamic parameters, intra-operative fentanyl consumption, duration of effective analgesia, visual analogue scale (VAS) scores at various time intervals, duration of motor block, and incidence of hemidiaphragmatic (HD) palsy. RESULTS: Total 24 h fentanyl consumption was significantly higher in Group B (558 ± 112 mcg) compared to Group A (296 ± 88 µg). Block onset was slower in Group B than Group A. There was no difference in intra-operative fentanyl consumption. Postoperative VAS scores were significantly higher in Group B compared to Group A, at 6 h and thereafter. Duration of motor block was significantly shorter in Group B (6.25 ± 1.25 h) compared to Group A. HD palsy was seen in all the cases in both the groups. CONCLUSION: Single shot nerve stimulator guided interscalene block with 10 ml of 0.5% ropivacaine was inferior to 20 mL of 0.5% ropivacaine with respect to postoperative analgesic efficacy.

A meta-analysis of randomized, placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults.

The efficacy and safety of vortioxetine, an antidepressant approved for the treatment of adults with major depressive disorder (MDD), was studied in 11 randomized, double-blind, placebo-controlled trials of 6/8 weeks׳ treatment duration. An aggregated study-level meta-analysis was conducted to estimate the magnitude and dose-relationship of the clinical effect of approved doses of vortioxetine (5-20mg/day). The primary outcome measure was change from baseline to endpoint in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Differences from placebo were analyzed using mixed model for repeated measurements (MMRM) analysis, with a sensitivity analysis also conducted using last observation carried forward. Secondary outcomes included MADRS single-item scores, response rate (≥50% reduction in baseline MADRS), remission rate (MADRS ≤10), and Clinical Global Impressions scores. Across the 11 studies, 1824 patients were treated with placebo and 3304 with vortioxetine (5mg/day: n=1001; 10mg/day: n=1042; 15mg/day: n=449; 20mg/day: n=812). The MMRM meta-analysis demonstrated that vortioxetine 5, 10, and 20mg/day were associated with significant reductions in MADRS total score (Δ-2.27, Δ-3.57, and Δ-4.57, respectively; p<0.01) versus placebo. The effects of 15mg/day (Δ-2.60; p=0.105) were not significantly different from placebo. Vortioxetine 10 and 20mg/day were associated with significant reductions in 9 of 10 MADRS single-item scores. Vortioxetine treatment was also associated with significantly higher rates of response and remission and with significant improvements in other depression-related scores versus placebo. This meta-analysis of vortioxetine (5-20mg/day) in adults with MDD supports the efficacy demonstrated in the individual studies, with treatment effect increasing with dose.

[Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate]. / Dosisfindung zur Behandlung mit transdermalem Fentanylpflaster : Titration mit oralem, transmukosalem Fentanylcitrat und Morphinsulfat.

To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

Fesoterodine clinical efficacy and safety for the treatment of overactive bladder in relation to patient profiles: a systematic review.

OBJECTIVE: To summarize published evidence on the pharmacology, efficacy, and safety of fesoterodine for the treatment of overactive bladder (OAB) symptoms in relation to patient clinical and demographic profiles. METHODS: A systematic review of published articles on fesoterodine was conducted via a PubMed search. Articles were identified using the search term fesoterodine, with limits of human species and abstract available. Review and meta-analysis articles, validation studies, articles focused on treatment compliance/adherence, meeting abstracts, and articles not focused on oral fesoterodine administration in human subjects were excluded. Data from retained articles were summarized descriptively. RESULTS: Of 137 articles identified, 61 (15 articles on the pharmacology and 46 articles on the efficacy and/or safety of fesoterodine) met inclusion criteria. Superiority trials demonstrated the additional efficacy of fesoterodine 8 mg versus fesoterodine 4 mg and tolterodine extended release 4 mg in treating OAB. Prospective trials in specific patient populations indicated beneficial effects of fesoterodine in elderly patients, vulnerable elderly patients, patients dissatisfied with or with a suboptimal response to previous antimuscarinic therapy, patients with urge urinary incontinence (UUI) or nocturnal urgency, and men with persistent LUTS during alpha-blocker treatment. With two effective doses, the fesoterodine dose can be adjusted to achieve optimal efficacy and tolerability in individual patients. The most common adverse events during fesoterodine treatment are dry mouth and constipation. CONCLUSIONS: Extensive evidence demonstrates the efficacy and safety of fesoterodine in relieving OAB symptoms, including urgency, urinary frequency, UUI, and nocturnal urgency, in patients with various clinical and demographic profiles. Trial results provide valuable information on fesoterodine treatment in specific patient populations, including both elderly and vulnerable elderly patients. Potential limitations of this review are that only English language articles in PubMed were searched and included.

The influence of 1α.25-dihydroxyvitamin d3 coating on implant osseointegration in the rabbit tibia.

OBJECTIVES: This study aims to evaluate bone response to an implant surface modified by 1α,25-dihydroxyvitamin D3 [1.25-(OH)2D3] in vivo and the potential link between 1.25-(OH) 2D3 surface concentration and bone response. MATERIAL AND METHODS: Twenty-eight implants were divided into 4 groups (1 uncoated control, 3 groups coated with 1.25-(OH)2D3 in concentrations of 10(-8), 10(-7) and 10(-6) M respectively), placed in the rabbit tibia for 6 weeks. Topographical analyses were carried out on coated and uncoated discs using interferometer and atomic-force-microscope (AFM). Twenty-eight implants were histologically observed (bone-to-implant-contact [BIC] and new-bone-area [NBA]). RESULTS: The results showed that the 1.25-(OH)2D3 coated implants presented a tendency to osseointegrate better than the non-coated surfaces, the differences were not significant (P > 0.05). CONCLUSIONS: The effect of 1.25-(OH)2D3 coating to implants suggested possible dose dependent effects, however no statistical differences could be found. It is thought that the base substrate topography (turned) could not sustain sufficient amount of 1.25-(OH)2D3 enough to present significant biologic responses. Thus, development a base substrate that can sustain 1.25-(OH)2D3 for a long period is necessary in future studies.